Method of treatment

ABSTRACT

One embodiment of the invention provides a method for administering tasimelteon to a human patient that comprises orally administering an effective dose of tasimelteon under fasted conditions. Fasted conditions may comprise administering the tasimelteon without food, no food at least 1/2 hour prior to administration, no food at least 1 hour prior to administration, no food at least 1-1/2 hours prior to administration, no food at least 2 hours prior to administration, no food at least 2-1/2 hours prior to administration, or no food at least 3 hours prior to administration. According to such embodiments, tasimelteon may be administered, for example, at a dose of 20 mg/d. Tasimelteon may be administered where, for example, the patient is being treated for a circadian rhythm disorder or for a sleep disorder, including, for example, Non-24 Disorder.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of co-pending U.S. patentapplication Ser. No. 14/511,669, filed 10 Oct. 2014, which claimspriority to then-co-pending US Provisional Application Serial Nos.61/927,465, filed 14 Jan. 2014, and 61/903,354, filed 12 Nov. 2013, eachof which is hereby incorporated herein as though fully set forth.

BACKGROUND OF THE INVENTION

Tasimelteon, and methods of using and processes for making tasimelteon,are disclosed in various references, including U.S. Pat. No. 5,856,529,US Patent Application Publication No. 20090105333, and US PatentApplication Publication No. 20130197076, copies of which are appendedhereto and are incorporated herein by reference as though fully setforth.

SUMMARY

One embodiment of the invention provides a method for administeringtasimelteon to a human patient that comprises orally administering aneffective dose of tasimelteon under fasted conditions. Fasted conditionsmay comprise administering the tasimelteon without food, no food atleast ½ hour prior to administration, no food at least 1 hour prior toadministration, no food at least 1-½ hours prior to administration, nofood at least 2 hours prior to administration, no food at least 2-½hours prior to administration, or no food at least 3 hours prior toadministration. According to such embodiments, tasimelteon may beadministered, for example, at a dose of 20 mg/d. Tasimelteon may beadministered where, for example, the patient is being treated for acircadian rhythm disorder or for a sleep disorder, including, forexample, Non-24 Disorder. Another embodiment of the invention provides amethod for administering tasimelteon to a human patient that comprisesinstructing the patient that tasimelteon should be taken without food.

Still another embodiment of the invention provides a method forshortening T_(max) in a human patient being treated with tasimelteon,said method comprising orally administering an effective dose oftasimelteon under fasted conditions.

In still yet another embodiment, the invention provides a method ofmarketing or selling tasimelteon that comprises informing prescribers,patients, and/or insurers that tasimelteon should be taken under fastedconditions, such as by including such instructions in printedprescribing information that is packaged with a container comprisingtasimelteon capsules.

BRIEF DESCRIPTION OF THE DRAWINGS

These and other features of this invention will be more readilyunderstood from the following detailed description of the variousaspects of the invention taken in conjunction with the accompanyingdrawings that depict various embodiments of the invention, in which:

FIG. 1 shows a flow diagram of a study related to the invention.

It is noted that the drawings of the invention are not to scale. Thedrawings are intended to depict only typical aspects of the invention,and therefore should not be considered as limiting the scope of theinvention.

DESCRIPTION OF THE INVENTION

This invention relates to administration of tasimelteon under fastedconditions, i.e., without food.

A clinical study was undertaken to investigate the effects of food onadministration of tasimelteon. Specifically, the primary objective ofthe study was to investigate the influence of food(high-calorie/high-fat) on the pharmacokinetics of 100 mg of tasimelteonin healthy subjects. This was a single-center, open-label, crossoverdesign which lasted up to 5 weeks. 26 Healthy male and female subjects(18-50 years old) were enrolled in the study. There was a 2-period,randomized, 2-sequence crossover design where each subject received 100mg tasimelteon either with or without food. Subjects were randomlyassigned to receive a 100 mg tasimelteon capsule under fasted conditionsor a 100 mg tasimelteon capsule under fed conditions (i.e., 30 minutesafter beginning to ingest a high-fat meal). There was a 7-day washoutbetween treatment groups. FIG. 1 depicts an example of the overall studydesign. In FIG. 1, tasimelteon is referred to as VEC-162.

For purposes of the study depicted in FIG. 1, administration underfasted conditions was administration with 240 mL of water atapproximately 6:00 AM, after at least a 10-hour fast.

Subjects were not allowed to eat any food for at least 4 hours postdose.Subjects were allowed to drink water as desired except 1 hour before and2 hours after drug administration.

Administration under fed conditions was administration with 240 mL ofwater at approximately 6:00 AM, after a high-fat/high=−caloriebreakfast, which included one cup of milk. Subjects began therecommended meal 30 minutes prior to drug administration. Subjectsfinished eating the meal in 30 minutes or less and the drug wasadministered approximately 30 minutes after the start of the meal.Subjects were not allowed to eat any food for at least 4 hours postdose.Subjects were allowed to drink water as desired except 1 hour before and2 hours after drug administration.

25 Subjects completed both periods of the study. Administration oftasimelteon with a high-fat/high-calorie meal resulted in a lowerC_(max) and longer T_(max). The mean C_(max) of 786±432 ng/mL underfasted conditions was reduced to a mean C_(max) of 445±255 ng/mL with ageometric mean ratio of 55.82% and an associated 90% confidence intervalof 49.72% to 62.67%. The extent of absorption, as measured byAUC_((0-t)) and AUC_((Inf)) was comparable under both fed and fastedconditions with geometric mean ratios of 108.57% and 106.54%,respectively, and 90% confidence intervals contained within the 80% to125% equivalence window. Consistent with a decrease in C_(max) and nochange in AUC, i.e., a decrease in the rate but not the extent ofabsorption, the median T_(max) increased from 0.75 hours under fastedconditions to 2.5 hours under fed conditions.

From this study, it was concluded that administration of tasimelteonwith a high-fat/high calorie meal results in a significant decrease inthe rate of absorption but no significant change in the extent ofabsorption.

Thus, in illustrative embodiments, the invention comprises:

a method for administering tasimelteon to a human patient that comprisesorally administering an effective dose of tasimelteon under fastedconditions;

a method for administering tasimelteon to a human patient that comprisesinstructing the patient that tasimelteon should be taken without food;

a method for shortening T_(max) in a human patient being treated withtasimelteon, said method comprising orally administering an effectivedose of tasimelteon under fasted conditions;

a method of marketing or selling tasimelteon that comprises informingprescribers, patients, and/or insurers that tasimelteon should be takenunder fasted conditions, such as by including such instructions inprinted prescribing information that is packaged with a containercomprising tasimelteon capsules.

In specific illustrative embodiments, the fasted conditions comprisesadministering the tasimelteon without food;

the fasted conditions comprises no food at least ½ hour prior toadministration;

the fasted conditions comprises no food at least 1 hour prior toadministration;

the fasted conditions comprises no food at least 1-½ hours prior toadministration;

the fasted conditions comprises no food at least 2 hours prior toadministration;

the fasted conditions comprises no food at least 2-½ hours prior toadministration; or

the fasted conditions comprises no food at least 3 hours prior toadministration;

In other illustrative embodiments, the Cmax is lowered while AUC isapproximately the same whether the drug is administered under fedconditions or under fasted conditions;

the dose of tasimelteon is 20 mg/d;

the patient is being treated for a circadian rhythm disorder or for asleep disorder; and/or

the patient is being treated for Non-24 Disorder.

Specific illustrative language for inclusion in the prescribinginformation (i.e., the “label”) might include, e.g.:

“The peak concentration (T_(max)) of tasimelteon occurred atapproximately 0.5 to 3 hours after fasted oral administration.

When administered with a high-fat meal, the C_(max) of tasimelteon was44% lower than when given in a fasted state, and the median T_(max) wasdelayed by approximately 1.75 hours. Therefore, HETLIOZ should be takenwithout food.”

What is claimed is:
 1. A method of treating a human patient sufferingfrom a circadian rhythm disorder or a sleep disorder, the methodcomprising: instructing the patient that tasimelteon should be takenwithout food; and orally administering to the patient an effective doseof tasimelteon without food.
 2. The method of claim 1, wherein thetasimelteon is administered with no food after at least ½ hour prior toadministration.
 3. The method of claim 1, wherein C_(max) of thetasimelteon is lowered while AUC is approximately the same whether thetasimelteon is administered under fed conditions or under fastedconditions.
 4. The method of claim 1, wherein the patient is sufferingfrom a circadian rhythm disorder.
 5. The method of claim 4, wherein thecircadian rhythm disorder is Non-24 Disorder.
 6. The method of claim 1,wherein the tasimelteon is administered with no food after at least onehour prior to administration.
 7. The method of claim 1, wherein thetasimelteon is administered with no food after at least one-and-one-halfhours prior to administration.
 8. The method of claim 1, wherein thetasimelteon is administered with no food after at least two hours priorto administration.
 9. The method of claim 1, wherein the tasimelteon isadministered with no food after at least two-and-one-half hours prior toadministration.
 10. The method of claim 1, wherein the tasimelteon isadministered with no food after at least three hours prior toadministration.
 11. The method of claim 1, wherein the effective dose is20 mg/d
 12. In a method of treating a human patient suffering from acircadian rhythm disorder or a sleep disorder by orally administering tothe patient 20 mg/d of tasimelteon once daily before a target bedtime,the improvement comprising: instructing the patient that tasimelteonshould be taken without food, wherein the patient has had no food for atleast ½ hour prior to the administering.
 13. The improvement of claim12, wherein the patient has had no food for at least one hour prior tothe administering.
 14. The improvement of claim 12, wherein the patienthas had no food for at least one-and-one-half hours prior to theadministering.
 15. The improvement of claim 12, wherein the patient hashad no food for at least two hours prior to the administering.
 16. Theimprovement of claim 12, wherein the patient has had no food for atleast two-and-one-half hours prior to the administering.
 17. Theimprovement of claim 12, wherein the patient has had no food for atleast three hours prior to the administering.
 18. A method of treating ahuman patient suffering from a circadian rhythm disorder or a sleepdisorder that comprises instructing the patient that tasimelteon shouldbe taken without food before orally administering to the patient aneffective dose of tasimelteon without food.
 19. The method of claim 18,wherein the effective dose is 20 mg/d.
 20. In a method of treating apatient with tasimelteon, the improvement comprising: instructing thepatient to take tasimelteon without food, and fasting at least 30minutes prior to taking the tasimelteon.